Adolescence marks a critical period for the onset of nicotine dependence in humans. The central theme of this proposal is that the inter-individual difference in sensation-seeking/risk-taking in adolescence is an antecedent to nicotine dependence with treatment implications for protecting against nicotine relapse. Using the novelty-seeking phenotype, a rat model of sensation-seeking in humans, high responder (HR) versus low responder (LR) rats are identified in a na[unreadable]ve, outbred population. The central hypothesis of this proposal is that adolescent HR animals will have robust and long-lasting neurobehavioral adaptations to chronic nicotine following a behavioral paradigm of locomotor sensitization to nicotine, and the cannabinoid receptor (CB) 1 antagonist will selectively normalize these adaptations. To validate this hypothesis, in Aim 1 an intermittent behavioral sensitization to nicotine paradigm will be used on phenotype pre-screened rats, and the therapeutic potential for the CB1 receptor antagonist AM251 will be compared to an FDA-approved smoking cessation agent bupropion and a mainstream 5HT1A receptor antagonist WAY 100635. In Aim 1a dose-effect curve for different doses of nicotine training will be established in locomotor response to a challenge dose of nicotine following nicotine abstinence. We will test the hypothesis that the HR but not LR animals manifest the expression of locomotor sensitization to nicotine challenge in response to mild dose of nicotine training regimen. In Aim 1b, we will test the hypothesis that AM251 administration during nicotine training or abstinence following training will inhibit the expression of behavioral sensitization in HRs. In Aim 1c, using different durations of nicotine abstinence, we will test the hypothesis that the expression of the locomotor sensitization to challenge nicotine in HRs lasts into young adulthood (60-90-d age), and AM251 administration up to 3rd week of abstinence can completely reverse this effect. In Aim 2, Timm's method for silver sulfide staining and contemporary stereology will be used to visualize and estimate volumes of the hippocampal mossy fibre terminal fields in response to adolescent nicotine with or without therapeutics on board. In Aim 2a, we will test the hypothesis that adolescent nicotine exposure selectively increases the hippocampal mossy fibre volume in the HRs with the peak of this effect being detected at the 3rd week following last nicotine exposure. In Aim 2b, we will test the hypothesis that treatment with AM251 during the active phase of remodeling (i.e., before plateu is reached) will completely reverse nicotine-induced changes in hippocampal mossy fibres in HRs. Validation of the central hypothesis will implicate CB1 receptor antagonists in treatment for nicotine relapse in vulnerable individuals. PUBLIC HEALTH RELEVANCE: Systematic investigation of individual differences in neurobiological makeup of nicotine dependence--especially during the dynamic period of adolescence--will lead to customized treatment options with better success in quitting smoking and prevention of relapse. This proposal and its kind are needed to cut down medical costs originating from switching treatment methods in search of the one that "works", and from deteriorating health conditions induced by relapsing back to chronic tobacco use such as cardiovascular disease and lung cancer.